Increasing renal salt reabsorption can cause a risk of hypertension. On the contrary, inhibition of renal reabsorption function can promote the excretion of urine, which results in diuretic and antihypertensive effects. Common diuretics are thiazide diuretics, which are first-line antihypertensive drugs in USA that primarily act on sodium-chloride (Na+—Cl)− transporters. The Loop diuretics are more effective for patients with impaired renal function, and they play a role through sodium-potassium-chloride (Na+—K+-2Cl−)— transfer proteins. However, both drugs can cause hypokalemia (symptoms: weakness, fatigue, muscle cramps, constipation, and heart rhythm problems, such as arrhythmia), which increases the risk of morbidity and mortality of cardiovascular disease.
Renal Outer Medullary Potassium channel (ROMK) is also known as the inward-rectifying potassium channel 1.1 (Kir1.1). The ROMK channel, cooperating with the Na+-K+-2Cl— co-transfer protein NKCC2 (responsible for NaCl transport) through the apical membrane conductance of the renal thick ascending limb (TAL), can regulate the reabsorption of potassium. The ROMK was found to be directly associated with the renal secretory channel. When the ROMK gene is knocked out in mice, there is a loss of TAL and CCD 35-pS ion channels as well as a loss of the other K+ channels. Batter syndrome is an autosomal recessive disease characterized by massive loss of salt in the kidneys, hypokalemia, and low blood pressure. Batter syndrome is mainly caused by mutations in the ROMK or Na+-K+-2Cl— co-transfer proteins. The difference is that the hypokalemia of the batter syndrome caused by the mutation of ROMK is much milder compared to that caused by the mutation of Na+-K+-2Cl— co-transfer proteins. In summary, inhibition of ROMK function can effectively inhibit the salt reabsorption function of Na+-K+-2Cl— co-transfer proteins and promote the excretion of urine, thereby resulting in diuretic and antihypertensive effects, without causing hypokalemia. Although a number of ROMK inhibitors have been disclosed at present, such as in PCT Patent Application Publications WO2010129379, WO2012058134, WO2012058116, WO2012058134, WO2013066714, WO2013028474, WO2014085210, WO2014018764, WO2014015495, WO2014085210, WO2013039802, WO2013062892 and WO2012058116, more compounds with better hERG selectivity need to be developed. The present invention provides a series of novel compounds represented by general formula (I), wherein a polar group is added, which can reduce ClogP, enhance the hERG selectivity and are much safer, while maintaining the ROMK inhibitory activity.